Identification of 5‐(3‐(methylsulfonyl)phenyl)‐3‐(4‐(methylsulfonyl)phenyl)‐ 3 H ‐imidazo[4,5‐ b ]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

• Published in: Chemical biology & drug design 2023-03, Vol.101 (3), p.690-695
• Main Authors: Kundu, Mrinalkanti, Dutta, Aditi, Roy, Kuldeep K., Mal, Sajal K., Karmakar, Shouvik, Mandal, Aritra, Mondal, Susanta K., Kumar, Sanjay, Saha, Soumya, Pradhan, Subhankar, Sarkar, Ratul, Chakrabarti, Monali, Malik, Pradip K., Banerjee, Manish
• Format: Article
• Language: English
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.14170

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin‐based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold‐hopping approach combined with docking studies for putative‐binding interactions with Plasmodium falciparum phosphatidylinositol‐4‐kinase ( Pf PI4K) target. The docking results steered to the synthesis of compound 1 [5‐(3‐(methylsulfonyl)phenyl)‐3‐(4‐(methylsulfonyl)phenyl)‐3 H ‐imidazo[4,5‐ b ]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME‐PK studies. Combined with potent antimalarial activity of compound 1 ( Pf 3D7 IC 50  = 29 nM) with meager in vitro intrinsic clearance, moderate plasma‐protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.